Advanced Sarcoma Research Articles

Inflammatory Surrogate Parameters for Predicting Ifosfamide-Induced Neurotoxicity in Sarcoma Patients.

Sarcomas compromise a heterogenous group of tumors of a mesenchymal origin. Although treatment options in many solid tumors have evolved over the past decades, the treatment of advanced sarcoma is still based on conventional chemotherapeutic agents. Beside anthracyclines, alkylating agents such as ifosfamide are frequently used in sarcoma treatment. However, treatment with ifosfamide can cause severe dose- and treatment-limiting side effects, such as ifosfamide-induced neurotoxicity (IIN). Especially in sarcoma, consecutive risk assessment analyses investigating the individual factors associated with the increased incidence in IIN, remain insufficient so far. In this retrospective analysis, we investigated 172 sarcoma patients treated with ifosfamide. Out of 172 patients, 49 patients (28.5%) developed IIN. While gender, age, histologic origin, and tumor stage were not associated with the occurrence of IIN, infusion times, simultaneous radiotherapy, and concomitant use of opioids or anticonvulsants affected the risk of developing IIN. Sarcoma patients with IIN showed an alteration in several inflammatory markers, including a lower lymphocyte count, hemoglobin levels, and calcium levels, as well as elevated GGT, sodium, and CRP levels. Remarkably, the occurrence of IIN was associated with a worse prognosis regarding progression free and overall survival. In addition, high CTCAE grades were negatively associated with overall survival in sarcoma. The observation that an inflammatory state is associated with an increased risk of IIN in sarcoma patients can be used prospectively to further investigate the relationship of inflammation and IIN. In addition, the easily accessible blood markers used in our study to predict IIN can be incorporated into clinical decision making.

Abstract A038: Enrollment of pediatric and adolescent patients with MAGE-A4+ advanced synovial sarcoma into cohort 2 of SPEARHEAD-1: a phase 2 trial of afamitresgene autoleucel (“afami-cel” [formerly ADP-A2M4

Abstract Background: Afami-cel is an autologous, specific peptide enhanced affinity receptor T-cell therapy genetically engineered to target MAGE-A4+ solid tumors in HLA-A*02+ patients. SPEARHEAD-1 (NCT04044768) is a Phase 2, two-cohort, single-arm, open-label trial evaluating afami-cel in patients with advanced/metastatic synovial sarcoma or myxoid/round cell liposarcoma (MRCLS) and is the largest trial in metastatic synovial sarcoma to date. Preliminary data from Cohort 1 in 47 heavily pre-treated patients aged 16–75 years from 22 centers in North America and Europe, showed an overall response rate (ORR) per independent review of 34.0% (14/39 [35.9%] in synovial sarcoma; 2/8 [25%] in MRCLS) and a favorable benefit–risk profile with mainly low-grade cytokine release syndrome and tolerable/reversible hematologic toxicities.1 The reported ORR in synovial sarcoma in Cohort 1 was higher than reported ORRs for current standard-of-care therapies, such as pazopanib and trabectedin, in the second-line metastatic setting.2 As synovial sarcoma is the most common malignant nonrhabdomyosarcoma soft-tissue sarcoma in children and adolescents with few treatment options, especially for recurrent disease, the trial opened a second cohort to allow enrollment of pediatric patients with MAGE-A4+ synovial sarcoma who experienced disease progression post first-line chemotherapy, and to better understand MAGE-A4 tumor expression in children. Methods: Cohort 2 of the SPEARHEAD-1 trial is enrolling patients with advanced synovial sarcoma who are at least 10 years old and weigh at least 40 kg. The planned enrollment is 45 patients, including up to 13 children, to enable a pooled analysis of ORR in >90 patients across Cohorts 1 and 2. HLA and MAGE-A4+ screening in Cohort 2 is conducted at a central laboratory using the same method as Cohort 1; MAGE-A4 testing is done using a clinical trial assay. All patients enrolled in Cohort 2 undergo apheresis and their isolated T-cells are then transduced with the MAGE-A4c1032 TCR using a lentivirus vector, followed by ex vivo expansion. Prior to afami-cel infusion of 1–10 × 109 transduced T-cells, patients will receive lymphodepleting chemotherapy consisting of fludarabine (30 mg/m2/day for 4 days) and cyclophosphamide (600 mg/m2/day for 3 days). Disease will be assessed by independent review per RECIST v1.1 using computerized tomography or magnetic resonance imaging at weeks 4, 8, 12, 16, 24, and every 2 months thereafter until confirmed disease progression. Patients enter long-term follow-up for 15 years. 1. Van Tine BA, et al. Paper 30: CTOS 2021; Virtual 2. Carroll C, et al. Cancer Res 2021;81(13_Suppl): Abstract nr 2630. Citation Format: Colin Lunt, Sandra P. D’Angelo, Albiruni Ryan Abdul Razak, Michael J. Wagner, Brian A. Van Tine, Kristen Ganjoo, Jean-Yves Blay, Dejka M. Araujo, Mark Agulnik, John W. Glod, Erin Van Winkle, Erica Elefant, Swethajit Biswas, Dennis Williams, Axel Le Cesne. Enrollment of pediatric and adolescent patients with MAGE-A4+ advanced synovial sarcoma into cohort 2 of SPEARHEAD-1: a phase 2 trial of afamitresgene autoleucel (“afami-cel” [formerly ADP-A2M4]) [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A038.

Abstract A022: Targeting of soft tissue sarcoma cancer stem cells improves doxorubicin-sensitivity in vitro

Abstract Soft tissue sarcomas (STS) are rare tumors encompassing over 70 distinct histopathological subtypes that share a common treatment strategy comprising surgical resection, radiation, and chemotherapy in certain situations. Disease progression and failure to respond to anthracycline based chemotherapy, a standard first-line agent, is associated with poor outcomes. Recurrence and chemo-resistance represent significant barriers to improving patient survival. We are interested in the contribution of STS cancer stem cells (STS-CSCs) to the phenomenon of chemo-resistance to doxorubicin. Specifically, we hypothesized the presence of a common genetic signature across unique STS subtypes involved in CSC-regulation that could be targeted to improve the efficacy of existing treatment regimens. To this end, STS-CSCs were profiled by flow cytometry using the Aldeflour assay. This is a well-established technique to measure the aldehyde dehydrogenase activity of cells which is high in the stem cell population. This fluorescently labels Aldefluor bright and dim cells as CSCs and non-CSCs, respectively. The abundance of the CSC population in several STS cell lines modeling dedifferentiated liposarcoma, leiomyosarcoma, and undifferentiated pleomorphic sarcoma were assessed by Aldeflour assay. In order to gain insight into the molecular pathways active in STS-CSCs, Aldeflour-bright and -dim populations were isolated by FACs and analyzed by RNA-sequencing. Gene-set enrichment analysis of genes upregulated in STS-CSCs identified a signature for the histone methyltransferase Enhancer of Zeste homolog 2 (EZH2), part of the polycomb repressive complex 2 (PRC2) responsible for H3K27 methylation. As an epigenetic modulator, increased EZH2 expression and activity potentiates decreased activity of genes involved in growth suppression and thereby has oncogenic activity. EZH2 can be inhibited with small molecules such as Tazemetostat, an approved treatment for metastatic and locally advanced epithelioid sarcoma. To test the effects of EZH2 inhibition on STS-CSCs, we first generated doxorubicin resistance STS cell lines by serial selection with increasing concentrations of doxorubicin. We identified a positive correlation between CSC abundance and doxorubicin IC50 in the resistant cell lines. Further, co-treatment of doxorubicin and tazemetostat was not only synergistic in the parent cell lines, but restored chemosensitivity in doxorubicin resistant lines. These data confirm the presence of shared genetic programs across distinct subtypes of STS that are unique to CSCs and amenable to therapeutic targeting. Citation Format: Edmond F. O'Donnell, Maria Muñoz, Lor Randall, Janai R. Carr-Ascher. Targeting of soft tissue sarcoma cancer stem cells improves doxorubicin-sensitivity in vitro [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A022.

Abstract A019: Phase 1, first-in-human, dose-expansion study of oral TP-1287, a cyclin dependent kinase 9 (CDK9) inhibitor, in patients with sarcoma

Abstract Background: CDK9 blockade inhibits tumor growth and progression by impairing the transcription of key oncogenes, such as MCL1 and MYC. TP-1287 is an orally delivered phosphate prodrug of the CDK9 inhibitor alvocidib. The anti-tumor activity of alvocidib has previously been shown in vitro in a Ewing sarcoma cell line and in vivo in a mouse Ewing sarcoma xenograft model. TP-1287 is being investigated in a phase 1 dose escalation and dose expansion study in patients with solid tumors (escalation) and sarcoma (expansion) (NCT03604783). The design of the expansion part of the phase 1 study in patients with sarcoma is herein described. Methods: Thirty patients with sarcoma will be enrolled. Key eligibility criteria are age ≥18 years (≥16 years if ≥40 kg); histologically confirmed locally advanced or metastatic unresectable Ewing sarcoma, dedifferentiated liposarcoma, or synovial sarcoma (10 patients each); 1–3 prior lines of therapy (including an anthracycline); Eastern Cooperative Oncology Group performance status of ≤1; acceptable liver and renal function, and acceptable hematologic and coagulation status. Exclusion criteria include a history of certain cardiovascular diseases (including heart failure and myocardial infarction [≤6 months]); seizure disorder requiring anticonvulsant therapy; presence of symptomatic central nervous system metastatic disease or disease that requires local therapy ≤2 weeks; severe chronic obstructive pulmonary disease with hypoxemia; active infections; or treatment with surgery, chemotherapy, or investigational therapy within 28 days or 5 half-lives (whichever occurs first). Patients will be treated at the recommended phase 2 dose established during dose escalation (11 mg twice daily orally, continuous dosing) and will continue to receive treatment with the same dose/schedule if they successfully complete a 28-day treatment cycle without significant treatment-related toxicity or progressive disease. Assessments will be performed on Day 1 and Day 15 of each cycle. Assessments for response and tumor burden will be done after Cycle 2 and at the end of every other cycle thereafter. The primary objective is objective response rate; secondary objectives are progression-free survival at 16 and 24 weeks and safety; and exploratory objectives are systemic exposure, antitumor activity (by objective radiographic assessment), and pharmacodynamics. Tumor tissue concentrations may be measured in patients who consent to optional tumor biopsies. Statistical analysis for all safety and efficacy parameters will be primarily descriptive in nature; time-to-event variables will be summarized via Kaplan-Meier. The dose expansion cohort is currently recruiting in the United States. Results: N/A. Conclusions: N/A. Citation Format: Andrew J. Wagner, Gregory M. Cote, Donald Richards, Nicholas J. Vogelzang, William J. Edenfield, Mitchell E. Gross, Lynn Mar, Gil D. Fine, Edward Dow, John A. Charlson. Phase 1, first-in-human, dose-expansion study of oral TP-1287, a cyclin dependent kinase 9 (CDK9) inhibitor, in patients with sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A019.

Durable Responses Using SNK01 Autologous Enhanced Natural Killer Cells and Pembrolizumab for Chemotherapy-Resistant Advanced Sarcoma: Case Reports, Review of Literature and Future Perspectives

Durable Responses Using SNK01 Autologous Enhanced Natural Killer Cells and Pembrolizumab for Chemotherapy-Resistant Advanced Sarcoma: Case Reports, Review of Literature and Future Perspectives

1497P Safety and efficacy of [90Y]Y-FAPI-46 radioligand therapy in patients with advanced sarcomas and other cancer entities

Several malignant solid tumors are characterized by high fibroblast activation protein alpha (FAPα) expression. FAPI-46 is a theranostic ligand for FAPα-directed PET imaging and subsequent radioligand therapy (RLT). We report efficacy and safety of 90Y-FAPI-46 RLT in patients with advanced sarcoma, pancreatic cancer (PDAC) and other cancer entities.

1522P Is it safe to discontinue the tyrosine kinase inhibitors in advanced sarcoma following a favorable tumor response to antiangiogenics therapy?

The use of novel antiangiogenic TKIs (AA-TKIs) has emerged as a major paradigm shift in recurrent sarcoma. Previous trials demonstrated an ORR of 8 ∼ 22% as monotherapy, and an ORR of 24∼29% as combination therapy against advanced sarcoma. However, it is still unknown whether a drug holiday of AA-TKIs is safe and feasible in patients with favorable response.

757P USFDA authorized compassionate use of SNK01 (autologous non-genetically modified natural killer cells with enhanced cytotoxicity) and checkpoint inhibitors in advanced heavily pre-treated sarcoma: A promising regimen

For patients (pts) with advanced sarcomas in the relapsed/refractory setting, few effective treatment options exist. The likelihood of response or tumor control diminishes with each subsequent line of therapy. Monotherapy of PD-L1 inhibitors has shown modest to no activity in sarcomas, especially in tumors with low or no PD-L1 expression. Natural killer (NK) cells have been implicated in the antitumor response to immune checkpoint inhibitors (CIs) with evidence suggesting a role in PD-L1-negative tumors.

1258P HJM-353: A potent, selective and orally bioavailable EED inhibitor with robust anti-tumor activities

Polycomb Repressive Complex 2 (PRC2), a multimeric complex that catalyzes the methylation of histone H3 at lysine 27 with core subunits EZH2, EED and SUZ12, functions as an epigenetic modulator in regulating cell proliferation and development. Dysregulation of the PRC2 complex is implicated in hematological and solid malignancies and shown to correlate with poor prognosis in cancers. Recently EZH2 inhibitor Tazemetostat has been approved by FDA for the treatment of advanced epithelioid sarcoma and follicular lymphoma. However, acquired resistant mutations in EZH2 and complementary activation of EZH1 might impair the effectiveness of this class of PRC2 inhibitors. Targeting the allosteric subunit EED represents a new strategy to fully inhibit PRC2 activity and address the limitations of EZH2 inhibition. Herein, we report HJM-353 as an efficacious EED inhibitor for cancer therapy. In vitro activities of HJM-353 were assessed by CTG assay and Western blot in EZH2 mutant human cell lines.In vivo anti-tumor activities of HJM-353 were evaluated in DLBCL and gastric cancer xenograft models.Pharmacokinetic/pharmacodynamics correlation of HJM-353 was determined by LC-MS/MS, Western blot and Q-PCR. HJM-353 effectively reduced H3K27me3 level and inhibited cell proliferation with an IC50 of 33.8 nM in WSU-DLCL2 cells. It displayed favorable PK properties and induced complete tumor regression in KARPAS-422 derived DLBCL xenograft model. Plasma concentration of HJM-353 correlated with the inhibition of H3K27me3 and upregulation of PRC2 target genes in tumors, indicating a clear PK/PD relationship in the xenografts. In addition, HJM-353 caused tumor stasis as MAK683 did in a xKATO-III gastric xenograft model. In summary, HJM-353 is a potent, selective and orally bioavailable EED inhibitor with robust anti-tumor activities. We are developing HJM-353 for the treatment of hematological malignancies and solid tumors and expect to file an IND in the second half of 2022.

Current status and prospects of anti-angiogenic small-molecule tyrosine kinase inhibitors in the therapy of soft tissue sarcoma

Chemotherapy is the main systemic treatment for patients with advanced soft tissue sarcoma, and immunotherapy is only effective for some special subtypes. Anti-angiogenic small molecule tyrosine kinase inhibitors represented by pazopanib and anlotinib are the main drugs of targeted therapy. They have been clearly recommended as the second-line treatment of non-specific soft tissue sarcoma in guidelines. In recent years, in addition to second-line monotherapy in patients with advanced sarcoma, some studies have been carried out in second-line combination therapy, maintenance therapy, first-line therapy and neoadjuvant therapy. This article briefly reviews the application status and prospect of anti-angiogenic small molecule tyrosine kinase inhibitors in advanced soft tissue sarcoma.

Retrospective study on the efficacy and safety of low dose apatinib in reversing chemotherapy resistance in sarcoma

Objective: To explore whether apatinib can reverse the chemotherapy resistance of patients with advanced sarcoma. Methods: The clinical data of advanced sarcoma patients after chemotherapy who received the original chemotherapy regimen combined with low-dose apatinib in Cancer Center of Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology from May 2018 to November 2021 were collected retrospectively to evaluate the efficacy and safety of this regimen. The primary end point was progression-free survival (PFS), and the secondary end points were objective response rate (ORR), disease control rate (DCR), overall survival (OS) and adverse events (AE). The patients were grouped according to the diagnosis: osteosarcoma, soft tissue sarcoma and undifferentiated small round cell sarcoma. And the benefits of combination treatment was investigated with the stratified analysis of best outcome of combined therapy, lines of chemotherapy received, best response and PFS of original chemotherapy. Results: A total of 30 patients were included in this study, including 20 males and 10 females. The mean age was (25.6±14.7) years. There were 9 cases of osteosarcoma, 11 cases of soft tissue sarcoma and 10 cases of undifferentiated small round cell sarcoma. No patient achieved complete response, 8 patients (26.7%) achieved partial response, 19 patients (63.3%) achieved disease stability, the ORR was 26.7%(8/30), and the DCR was 90.0%(27/30). The median PFS and OS were 4.1 and 13.1 months respectively. Among the three different subtypes of sarcoma, the ORR of osteosarcoma was 44.4% (4/9), the median PFS was 4.1 months, and the median OS was not yet achieved; the ORR of undifferentiated small round cell sarcoma was 40% (4/10), the median PFS was 6.4 months, and the median OS was 10.9 months; No response was observed in soft tissue sarcoma, and the median PFS and median OS was 3.5 and 7.3 months respectively. Patients who achieved objective response had better PFS than patients with stable disease (12.8 vs 3.8 months, P=0.015), and patients with PFS≥ 6 months of original chemotherapy had better PFS benefits (12.7 vs 2.7 months, P<0.001). However, the number of original chemotherapy lines and the best response of original chemotherapy had no significant effect on the PFS of this combination regimen. In terms of safety, the related toxicity of apatinib was no more than grade 2, and the grade 4 chemotherapy-related adverse reactions was mainly hematological toxicity, of which 2 patients interrupted treatment because of febrile neutropenia. Conclusion: Low dose apatinib is effective in reversing chemotherapy resistance of osteosarcoma and undifferentiated small round cell sarcoma with acceptable adverse reactions.

PD-1/L1 inhibitor plus chemotherapy in the treatment of sarcomas.

There is an urgent clinical need for new therapeutic regimens for the effective treatment of advanced sarcomas. Accumulating evidence suggests that programmed death receptor-1/programmed death protein ligand-1 (PD-1/L1) inhibitors have synergistic effects with chemotherapy and have been approved for treatment of lung cancer, gastroesophageal cancer, and breast cancer. In this review, we reviewed the synergistic mechanism of PD-1/L1 inhibitors plus chemotherapy in the treatment of cancers, and the application of this combined regimen in several cancers, followed by a summary of the current evidence on the application of this combined regimen in the treatment of sarcomas as well as the main clinical trials currently underway. Based on the findings of this review, we believe that this combined approach will play an important role in the treatment of some subtypes of sarcomas in the future.

Extremely rare primary undifferentiated pleomorphic thyroid sarcoma-Clinical case with a literary review

Anaplastic thyroid carcinoma (ATC) known as undifferentiated and dedifferentiated carcinoma, is a rare, highly aggressive neoplasm. We present an extremely fast growing undifferentiated pleomorphic sarcoma originating in the thyroid gland in an 80-year-old woman. Through this clinical case, we show the importance of the pathohistological characteristic and immunohistochemical analysis for diagnosis of these extremely malignant neoplasms. Due to the radiation- and chemoresistance of this malignant undifferentiated soft tissue neoplasm, early diagnosis for a small tumor volume without distant hematogenous metastases is required to perform maximum radical surgery. Locally advanced sarcomas with lung metastases are subject to symptomatic and palliative treatment and the prognosis is very unfavorable.

Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: a single-centre phase 2 trial

Few standard treatment options are available for patients with metastatic sarcomas. We did this trial to evaluate the efficacy, safety, and changes in the tumour microenvironment for durvalumab, an anti-PD-L1 drug, and tremelimumab, an anti-CTLA-4 drug, across multiple sarcoma subtypes. In this single-centre phase 2 trial, done at The University of Texas MD Anderson Cancer Center (Houston, TX USA), patients aged 18 years or older with advanced or metastatic sarcoma with an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least one previous line of systemic therapy were enrolled in disease subtype-specific groups (liposarcoma, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma, synovial sarcoma, osteosarcoma, alveolar soft-part sarcoma, chordoma, and other sarcomas). Patients received 1500 mg intravenous durvalumab and 75 mg intravenous tremelimumab for four cycles, followed by durvalumab alone every 4 weeks for up to 12 months. The primary endpoint was progression-free survival at 12 weeks in the intention-to-treat population (all patients who received at least one dose of treatment). Safety was also analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02815995, and is completed. Between Aug 17, 2016, and April 9, 2018, 62 patients were enrolled, of whom 57 (92%) received treatment and were included in the intention-to-treat population. With a median follow-up of 37·2 months (IQR 1·8-10·1), progression-free survival at 12 weeks was 49% (95% CI 36-61). 21 grade 3-4 treatment-related adverse events were reported, the most common of which were increased lipase (four [7%] of 57 patients), colitis (three [5%] patients), and pneumonitis (three [5%] patients). Nine (16%) patients had a treatment related serious adverse event. One patient had grade 5 pneumonitis and colitis. The combination of durvalumab and tremelimumab is an active treatment regimen for advanced or metastatic sarcoma and merits evaluation in specific subsets in future trials. AstraZeneca.

Vascular reconstructions associated with monobloc resection of soft tissue sarcomas: A monocentric experience

Patients presenting locally advanced or recurrent sarcomas require extended surgical resections, sometimes in an irradiated zone and with a vascular invasion in approximately 5% of the cases, and are treated in reference centers. The objective of this study was to evaluate the results of oncovascular surgery (OVS) in patients presenting a soft tissue retroperitoneal or limb sarcoma.

Safety and Efficacy of 90Y-FAPI-46 Radioligand Therapy in Patients with Advanced Sarcoma and Other Cancer Entities.

We report efficacy and safety of 90Y-labeled FAPI-46 (90Y-FAPI-46-RLT) in patients with advanced sarcoma, pancreatic cancer, and other cancer entities. Up to four cycles of radioligand therapy (RLT) were offered to patients with (i) progressive metastatic malignancy, (ii) exhaustion of approved therapies, and (iii) high fibroblast activation protein (FAP) expression, defined as SUVmax ≥ 10 in more than 50% of tumor. Primary endpoint was RECIST response after RLT. Secondary endpoints included PET response (PERCIST), overall survival (OS), dosimetry, and safety of FAP-RLT. Among 119 screened patients, 21 (18%) were found eligible [n = 16/3/1/1 sarcoma/pancreatic cancer/prostate/gastric cancer; 38% Eastern Cooperative Oncology Group (ECOG) ≥ 2] and received 47 90Y-FAPI-46-RLT cycles; 16 of 21 (76%) patients underwent repeat RLT. By RECIST, disease control was confirmed in 8 of 21 patients [38%; 8/16 (50%) of evaluable patients). There was one partial response (PR) and seven stable diseases after RLT. Disease control was associated with prolonged OS (P = 0.013). PERCIST response was noted in 8 of 21 patients [38%; 8/15 (53%) of evaluable patients]. Dosimetry was acquired in 19 (90%) patients. Mean absorbed dose was 0.53 Gy/GBq in kidney, 0.04 Gy/GBq in bone marrow, and <0.14 Gy/GBq in liver and lung. Treatment-related grade 3 or 4 adverse events were observed in 8 (38%) patients with thrombocytopenia (n = 6) and anemia (n = 6) being most prevalent. 90Y-FAPI-46-RLT was safe and led to RECIST PR in one case as well as stable disease in about one third of patients with initially progressive sarcomas, pancreatic cancer, and other cancers. Discontinuation after the first cycle and a low rate of PR requires future improvement of FAP-RLT.

Evaluation of four chemotherapy regimens for treatment of advanced AIDS-associated Kaposi sarcoma in Kenya: a cost-effectiveness analysis

The most effective treatment for advanced AIDS-associated Kaposi sarcoma is paclitaxel or pegylated liposomal doxorubicin (PLD); neither is routinely used in sub-Saharan Africa due to limited availability and high cost. We examined the clinical impact, costs, and cost-effectiveness of paclitaxel or PLD in Kenya, compared with etoposide or bleomycin-vincristine. In this study, we use the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-International Model to project clinical outcomes and costs among people living with HIV and advanced Kaposi sarcoma on antiretroviral therapy. We compared four different treatment strategies: etoposide, bleomycin-vincristine, paclitaxel, or PLD. We derived cohort characteristics and costs from the Kenyan Academic Model for Providing Access to Healthcare network, and adverse events, efficacy, and mortality from clinical trials. We projected model outcomes over a lifetime and included life expectancy, per-person lifetime costs, and incremental cost-effectiveness ratios (ICERs). We conducted budget impact analysis for 5-year total costs and did deterministic and probabilistic sensitivity analyses to evaluate the effect of uncertainty in input parameters. We found that paclitaxel would be more effective than bleomycin-vincristine and would increase life expectancy by 4·2 years per person. PLD would further increase life expectancy by 0·6 years per person. Paclitaxel would be the most cost-effective strategy (ICER US$380 per year-of-life-saved compared with bleomycin-vincristine) and would remain cost-effective across a range of scenarios. PLD would be cost-effective compared with paclitaxel if its price were reduced to $100 per cycle (base case $180 per cycle). Implementing paclitaxel instead of bleomycin-vincristine would save approximately 6400 life-years and would increase the overall 5-year Kenyan health-care costs by $3·7 million; increased costs would be primarily related to ongoing HIV care given improved survival. Paclitaxel would substantially increase life expectancy and be cost-effective compared with bleomycin-vincristine for advanced AIDS-associated Kaposi sarcoma in Kenya and should be the standard of care. PLD would further improve survival and be cost-effective with a 44% price reduction. US National Institutes of Health and Massachusetts General Hospital. For the Swahili translation of the abstract see Supplementary Materials section.

The Role of AKT in Soft Tissue Sarcoma: Review and Insights.

Soft tissue sarcomas (STS) are a biologically diverse group of mesenchymal tumors that predominantly exhibit a poor prognosis. Surgical resection is considered the mainstay of treatment and provides the only chance for long-term survival. However, some patients present with locally advanced, unresectable disease, and for those who are able to undergo resection, tumor recurrence occurs in over half of patients. In addition, the efficacy of conventional systemic therapies remains dismal. The serine/threonine kinase AKT pathway is one of the most frequently aberrantly activated signaling pathways that has been verified in many types of human cancer. Dysregulation of the AKT cascade is known to result in tumorigenesis and aggressive clinical behavior for many tumor types, including STS. EGFRs, with its downstream effectors, PI3K and protein kinase B (AKT)/mTOR, have been investigated for decades as promising targets for the treatment of STS, but significant challenges remain and the prognosis of patients with advanced STS has not improved in over two decades. In this review, we will first describe the AKT pathway and its role in STS tumor biology and then discuss the current challenges in targeting the AKT pathway to treat patients with advanced sarcoma.

A Multicentre Clinical Study of Sarcoma Personalised Treatment Using Patient-Derived Tumour Xenografts

AimsMedication for advanced sarcomas has not improved for three decades. Patient-derived tumour xenografts (PDTX) are a promising solution for developing new therapies and real-time personalised medicine because of their highly effective prediction of drug efficacy. However, there is a dearth of PDTX models for sarcomas due to the scarcity and heterogeneity of the disease. Materials and methodsA multicentre clinical collaborative study (ChiCTR–OOC–17013617) was carried out. Fresh patient tumour tissues via resection or biopsy were used for the PDTX set-up. The standard medical care chosen by the physician was given to the patient, in parallel with testing on multiple regimens. The outcomes of patients' responses and PDTX tests were compared. Comprehensive analyses were carried out to assess the clinical value of PDTX for the treatment of sarcomas. Living tissues from successfully engrafted cases were deposited into a repository. ResultsForty-two cases, including 36 bone sarcomas and six soft-tissue sarcomas, were enrolled; the overall engraftment rate was 73.8%. Histopathological examination showed a 100% consistency between primary tumours and tumour grafts. The engraftment rate was independent of age, gender and sampling methods, but was associated with subtypes of tumour. The outgrowth time of tumour grafts could be associated with prognosis. Major somatic mutations in tumour grafts occurred primarily in common tumour driver genes. Poor prognosis was associated with the KMT2C mutation. A drug efficacy test showed complete concordance between the PDTX model and patients' responses in 17 regimens. ConclusionPDTX is an ideal preclinical model for sarcomas because of its faithful preservation of the heterogeneity of the disease, a satisfactory engraftment rate and high accuracy in its prediction of drug efficacy.

Chemical biology and pharmacology of histone lysine methylation inhibitors

Histone lysine methylation is a post-translational modification that plays a key role in the epigenetic regulation of a broad spectrum of biological processes. Moreover, the dysregulation of histone lysine methyltransferases (KMTs) has been implicated in the pathogenesis of several diseases particularly cancer. Due to their pathobiological importance, KMTs have garnered immense attention over the last decade as attractive therapeutic targets. These endeavors have culminated in tens of chemical probes that have been used to interrogate many aspects of histone lysine methylation. Besides, over a dozen inhibitors have been advanced to clinical trials, including the EZH2 inhibitor tazemetostat approved for the treatment of follicular lymphoma and advanced epithelioid sarcoma. In this Review, we highlight the chemical biology and pharmacology of KMT inhibitors and targeted protein degraders focusing on the clinical development of EZH1/2, DOT1L, Menin-MLL, and WDR5-MLL inhibitors. We also briefly discuss the pharmacologic targeting of other KMTs.